Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou, 310009, China.
Acta Pharmacol Sin. 2019 Oct;40(10):1343-1350. doi: 10.1038/s41401-019-0262-4. Epub 2019 Jul 11.
Emerging evidence indicates that M2-polarized tumor-associated macrophages (TAMs) directly participate in tumor initiation, progression and metastasis. However, to date, few studies have investigated novel strategies for inhibiting TAMs in order to overcome osteosarcoma. In this study, we reported that M2 macrophages were enriched in osteosarcoma tissues from patients, and M2-polarized TAMs enhanced cancer initiation and stemness of osteosarcoma cells, thereby establishing M2-polarized TAMs as a therapeutic target for blocking osteosarcoma formation. We also found that all-trans retinoic acid (ATRA) weakened TAM-induced osteosarcoma tumor formation by inhibiting M2 polarization of TAMs in vivo, and inhibited the colony formation, as well as sphere-formation capacity of osteosarcoma cells promoted by M2-type macrophages in vitro. Furthermore, M2-type macrophages enhanced cancer stem cells (CSCs) properties as assessed by increasing the numbers of CD117Stro-1 cells accompanied by the upregulation of CSC markers (CD133, CXCR4, Nanog, and Oct4), which could clearly be reduced by ATRA. Taken together, the results of this study demonstrated the role of M2-polarized TAMs in osteosarcoma initiation and stemness by activating CSCs, and indicated that ATRA treatment is a promising approach for treating osteosarcoma by preventing M2 polarization of TAMs.
新出现的证据表明，M2 极化的肿瘤相关巨噬细胞（TAMs）直接参与肿瘤的发生、进展和转移。然而，迄今为止，很少有研究探讨抑制 TAMs 的新策略，以克服骨肉瘤。在这项研究中，我们报告说 M2 巨噬细胞在患者的骨肉瘤组织中富集，M2 极化的 TAMs 增强了骨肉瘤细胞的起始和干性，从而将 M2 极化的 TAMs 确立为阻断骨肉瘤形成的治疗靶点。我们还发现，全反式维甲酸（ATRA）通过抑制体内 TAMs 的 M2 极化来减弱 TAM 诱导的骨肉瘤肿瘤形成，并抑制 M2 型巨噬细胞在体外促进的骨肉瘤细胞集落形成和球体形成能力。此外，M2 型巨噬细胞通过增加 CD117Stro-1 细胞的数量来增强癌症干细胞（CSC）特性，同时上调 CSC 标志物（CD133、CXCR4、Nanog 和 Oct4），而 ATRA 可明显降低这些标志物的水平。总之，这项研究的结果表明，M2 极化的 TAMs 通过激活 CSCs 在骨肉瘤起始和干性中发挥作用，并表明 ATRA 治疗通过防止 TAMs 的 M2 极化是治疗骨肉瘤的一种有前途的方法。
